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Transplantation and Cellular Therapy Mar 2023Transplantation-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplantation (HCT) associated with...
Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and...
Transplantation-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplantation (HCT) associated with significant morbidity and mortality. However, TA-TMA is a clinical diagnosis, and multiple criteria have been proposed without universal application. Although some patients have a self-resolving disease, others progress to multiorgan failure and/or death. Poor prognostic features also are not uniformly accepted. The lack of harmonization of diagnostic and prognostic markers has precluded multi-institutional studies to better understand incidence and outcomes. Even current interventional trials use different criteria, making it challenging to interpret the data. To address this urgent need, the American Society for Transplantation and Cellular Therapy, Center for International Bone Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation nominated representatives for an expert panel tasked with reaching consensus on diagnostic and prognostic criteria. The panel reviewed literature, generated consensus statements regarding diagnostic and prognostic features of TA-TMA using the Delphi method, and identified future directions of investigation. Consensus was reached on 4 key concepts: (1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue; however, biopsy is not required; (2) consensus diagnostic criteria are proposed using the modified Jodele criteria with additional definitions of anemia and thrombocytopenia. TA-TMA is diagnosed when ≥4 of the following 7 features occur twice within 14 days: anemia, defined as failure to achieve transfusion independence despite neutrophil engraftment; hemoglobin decline by ≥1 g/dL or new-onset transfusion dependence; thrombocytopenia, defined as failure to achieve platelet engraftment, higher-than-expected transfusion needs, refractory to platelet transfusions, or ≥50% reduction in baseline platelet count after full platelet engraftment; lactate dehydrogenase (LDH) exceeding the upper limit of normal (ULN); schistocytes; hypertension; soluble C5b-9 (sC5b-9) exceeding the ULN; and proteinuria (≥1 mg/mg random urine protein-to-creatinine ratio [rUPCR]); (3) patients with any of the following features are at increased risk of nonrelapse mortality and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2 times the ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II-IV acute graft-versus-host disease (GVHD), or infection (bacterial or viral); and (4) all allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. Patients diagnosed with TA-TMA should be risk-stratified, and those with high-risk disease should be offered participation in a clinical trial for TA-TMA-directed therapy if available. We propose that these criteria and risk stratification features be used in data registries, prospective studies, and clinical practice across international settings. This harmonization will facilitate the investigation of TA-TMA across populations diverse in race, ethnicity, age, disease indications, and transplantation characteristics. As these criteria are widely used, we expect continued refinement as necessary. Efforts to identify more specific diagnostic and prognostic biomarkers are a top priority of the field. Finally, an investigation of the impact of TA-TMA-directed treatment, particularly in the setting of concurrent highly morbid complications, such as steroid-refractory GVHD and infection, is critically needed.
Topics: Humans; Child; Prognosis; Bone Marrow; Prospective Studies; Thrombotic Microangiopathies; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease
PubMed: 36442770
DOI: 10.1016/j.jtct.2022.11.015 -
International Journal of Laboratory... Apr 2012Schistocytes are fragments of red blood cells (RBCs) produced by extrinsic mechanical damage within the circulation. The detection of schistocytes is an important...
Schistocytes are fragments of red blood cells (RBCs) produced by extrinsic mechanical damage within the circulation. The detection of schistocytes is an important morphological clue to the diagnosis of thrombotic microangiopathic anemia (TMA). Reporting criteria between different laboratories, however, are not uniform, owing to variability of shape and nature of fragments, as well as subjectivity and heterogeneity in their morphological assessment. Lack of standardization may lead to inconsistency or misdiagnosis, thereby affecting treatment and clinical outcome. The Schistocyte Working Group of the International Council for Standardization in Haematology (ICSH) has prepared specific recommendations to standardize schistocyte identification, enumeration, and reporting. They deal with the type of smear, method of counting, morphological description based on positive criteria (helmet cells, small, irregular triangular, or crescent-shaped cells, pointed projections, and lack of central pallor). A schistocyte count has a definite clinical value for the diagnosis of TMA in the absence of additional severe red cell shape abnormalities, with a confident threshold value of 1%. Automated counting of RBC fragments is also recommended by the ICSH Working Group as a useful complement to the microscope, according to the high predictive value of negative results, but worthy of further research and with limits in quantitation.
Topics: Erythrocyte Count; Erythrocytes, Abnormal; Humans; Purpura, Thrombotic Thrombocytopenic
PubMed: 22081912
DOI: 10.1111/j.1751-553X.2011.01380.x -
Indian Journal of Hematology & Blood... Apr 2020The occurrence of thrombotic microangiopathy (TMA) in pregnancy is an unfortunate emergency condition. Proper diagnosis is mandatory which requires the consideration of...
Combined Immature Platelet Fraction and Schistocyte Count to Differentiate Pregnancy-Associated Thrombotic Thrombocytopenic Purpura from Severe Preeclampsia/Haemolysis, Elevated Liver Enzymes, and Low Platelet Syndrome (SPE/HELLP).
The occurrence of thrombotic microangiopathy (TMA) in pregnancy is an unfortunate emergency condition. Proper diagnosis is mandatory which requires the consideration of two overlapping diagnoses: severe preeclampsia/haemolysis, elevated liver enzymes, and low platelet syndrome (SPE/HELLP) and thrombotic thrombocytopenic purpura (TTP). The long turn-around times of ADAMTS13 testing precludes the timely distinction between the two conditions. We aimed at evaluating schistocyte counts and immature platelet fraction (IPF%), as both increase in TMAs, to discriminate between TTP and SPE/HELLP of pregnancy. IPF% was measured using Sysmex XE-2100 automated hematology analyzer, and schistocyte counts were estimated microscopically as per the International Council for Standardization in Hematology-Schistocyte Working Group guidelines. The study included 30 pregnant patients with SPE/HELLP, 13 pregnant patients with TTP, and 30 women with normal pregnancy. The discrimination between the two patient categories was based on clinical judgment and TTP cases were identified using the PLASMIC score. TTP patients had higher values of IPF% than SPE/HELLP [19.5% (16.9-27.1) vs 13% (9.5-23.25); < 0.001]; similar results were revealed regarding schistocyte counts [6.5% (3.9-8.6) vs 2.1% (1.6-3.5); < 0.001]. IPF% and schistocyte counts were able to discriminate between TMA patients and normal pregnant women, and between and SPE/HELLP and TTP patients. Moreover, the discriminatory function of each was improved when the two parameters were used in combination. IPF% analysis should be used in conjunction with manual schistocyte counting in TMA cases to distinguish TTP pregnant patients from patients having SPE/HELLP.
PubMed: 32425383
DOI: 10.1007/s12288-019-01200-y -
Toxins Jan 2022Snakebite is a significant and under-resourced global public health issue. Snake venoms cause a variety of potentially fatal clinical toxin syndromes, including... (Review)
Review
Snakebite is a significant and under-resourced global public health issue. Snake venoms cause a variety of potentially fatal clinical toxin syndromes, including venom-induced consumption coagulopathy (VICC) which is associated with major haemorrhage. A subset of patients with VICC develop a thrombotic microangiopathy (TMA). This article reviews recent evidence regarding snakebite-associated TMA and its epidemiology, diagnosis, outcomes, and effectiveness of interventions including antivenom and therapeutic plasma-exchange. Snakebite-associated TMA presents with microangiopathic haemolytic anaemia (evidenced by schistocytes on the blood film), thrombocytopenia in almost all cases, and a spectrum of acute kidney injury (AKI). A proportion of patients require dialysis, most survive and achieve dialysis free survival. There is no evidence that antivenom prevents TMA specifically, but early antivenom remains the mainstay of treatment for snake envenoming. There is no evidence for therapeutic plasma-exchange being effective. We propose diagnostic criteria for snakebite-associated TMA as anaemia with >1.0% schistocytes on blood film examination, together with absolute thrombocytopenia (<150 × 10/L) or a relative decrease in platelet count of >25% from baseline. Patients are at risk of long-term chronic kidney disease and long term follow up is recommended.
Topics: Humans; Snake Bites; Thrombotic Microangiopathies
PubMed: 35051033
DOI: 10.3390/toxins14010057 -
Clinical and Experimental Medicine Jul 2023The COVID-19 pandemic caused by SARS-CoV-2 continues to spread rapidly due to its virulence and ability to be transmitted by asymptomatic infected persons. If they are... (Review)
Review
The COVID-19 pandemic caused by SARS-CoV-2 continues to spread rapidly due to its virulence and ability to be transmitted by asymptomatic infected persons. If they are present, the symptoms of COVID-19 may include rhinorrhea (runny nose), headache, cough, and fever. Up to 5% of affected persons may experience more severe COVID-19 illness, including severe coagulopathy, acute respiratory distress syndrome (ARDS) characterized by respiratory failure that requires supplementary oxygen and mechanical ventilation, and multi-organ failure. Interestingly, clinical evidence has highlighted the distinction between COVID-19-associated coagulopathy (CAC) and disseminated intravascular coagulation (DIC). Patients with CAC exhibit different laboratory values than DIC patients for activated partial thromboplastin time (aPTT) and prothrombin time (PT) which may be normal or shortened, varying platelet counts, altered red blood cell morphology, unique bleeding complications, a lack of schistocytes in the peripheral blood, and no decrease in fibrinogen levels. In this review, we consider the search for 1) laboratory results that can diagnose or predict development of CAC, including serum levels of D-dimers, fibrinogen, interleukin-6 (IL-6) and the growth factor angiopoietin-2 (Ang-2), 2) mechanisms of CAC induction, and 3) novel therapeutic regimens that will successfully treat COVID-19 before development of CAC.
Topics: Humans; COVID-19; SARS-CoV-2; Pandemics; Blood Coagulation Disorders; Fibrinogen
PubMed: 36121504
DOI: 10.1007/s10238-022-00891-4 -
Open Access Emergency Medicine : OAEM 2022Immune thrombocytopenia (ITP) is characterized by a platelet count less than 100 × 10^9/L without anemia or leukopenia. Patients with ITP may be asymptomatic, or... (Review)
Review
Immune thrombocytopenia (ITP) is characterized by a platelet count less than 100 × 10^9/L without anemia or leukopenia. Patients with ITP may be asymptomatic, or they may have mild bleeding like petechiae, purpura, or epistaxis. In rare cases, they may present to the emergency department (ED) with life-threatening bleeding as a result of their thrombocytopenia. The emergency physician should thus be prepared to diagnose ITP and treat the bleeding that can result from it. The diagnosis of ITP requires excluding secondary causes of thrombocytopenia, and in the ED, the bare minimum workup for ITP includes a complete blood count and a peripheral blood smear. The peripheral blood smear should show a small number of large platelets with normal morphology, and there should not be an increased number of schistocytes. Many patients with ITP require no emergent treatment. However, if a patient with suspected ITP presents to the ED with critical hemorrhage, the emergency physician should initiate treatment with a platelet transfusion, corticosteroids, and intravenous immune globulin (IVIG) as soon as possible. For less severe bleeding, platelet transfusions are not recommended, and the treatment consists of corticosteroids by themselves or in conjunction with IVIG.
PubMed: 35125895
DOI: 10.2147/OAEM.S331675 -
Cureus Jul 2020A 73-year-old female with past medical history of essential hypertension, hyperlipidemia, seasonal allergies, and chronic back pain presented to the hospital with...
A 73-year-old female with past medical history of essential hypertension, hyperlipidemia, seasonal allergies, and chronic back pain presented to the hospital with complaints of headaches, fevers, fatigue, generalized body aches, shortness of breath, and diarrhea. Initial complete blood count was remarkable for leukopenia with an absolute lymph count of 0.60 K/µL and severe thrombocytopenia (platelet count < 3 K/µL). She was tested for COVID-19 via nasopharyngeal swab polymerase chain reaction (PCR) testing and found positive. Additional labs showed an elevated D-dimer, C-reactive protein, fibrinogen, and lactate dehydrogenase. Vitamin B12 and folate levels were obtained and found to be normal. Peripheral smear showed no schistocytes or additional hematologic abnormalities apart from thrombocytopenia. The patient was transfused one unit of platelets with no improvement in platelet count. Fibrinogen count was obtained and found in normal range at 458 mg/dL. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) were all found to be normal. Immune thrombocytopenia purpura (ITP) was suspected and intravenous immunoglobulin (IVIG) was administered at a dose of 1 g/kg/day for two doses. By day 4, the patient had marked response to treatment with platelet recovery to 105 K/µL and subsequently discharged by day 5 with complete resolution of symptoms and platelet count of 146 K/µL. Twenty-eight days after discharge, she presented to hematology clinic with platelet count of 8 K/µL. Repeat nasopharyngeal swab PCR COVID testing was negative and she was treated with IVIG and pulse dexamethasone with prompt response, confirming suspicion of underlying, undiagnosed ITP prior to COVID infection.
PubMed: 32676257
DOI: 10.7759/cureus.9083 -
Pathology Oct 2021Schistocytosis is the morphological hallmark of the microangiopathic haemolytic anaemia of thrombotic microangiopathy (TMA). Consensus guidelines for manual schistocyte...
Schistocytosis is the morphological hallmark of the microangiopathic haemolytic anaemia of thrombotic microangiopathy (TMA). Consensus guidelines for manual schistocyte quantitation are available, but limited research has evaluated them. The 2012 International Council for Standardization in Haematology (ICSH) recommends a schistocyte quantitation of 1% as a robust cut-off for significance, with the quantitation including helmet, crescent, triangle and keratocyte poikilocytes; and microspherocytes only in the presence of helmets, crescents/triangles, and keratocytes. We aimed to evaluate the relative contribution of these different poikilocytes to schistocyte counting; compare the ICSH method with our proposed method which counts only cells most specific for red cell fragmentation (helmet, crescent and triangular schistocytes); and evaluate inter- and intra-observer agreement. Blood films were sourced from the Australian Snakebite Project, including non-envenomed and envenomed cases, with and without TMA. In blood films across the range of schistocytosis, the predominant poikilocytes present were helmets and crescents. Triangles, keratocytes and microspherocytes were typically only present when ICSH schistocyte count was >1%. With results dichotomised as <1.0% or ≥1.0%, our proposed new method versus the ICSH method showed almost perfect agreement [observed agreement 95%, Cohen's kappa (κ)=0.84, SE 0.04, 95% CI 0.76-0.92, p<0.005]. Inter-observer strength of agreement for our method was moderate (Fleiss' κ for comparisons between three non-unique microscopists κ=0.50, SE 0.05, 95% CI 0.41-0.59, p<0.005). Intra-observer reproducibility assessed in two microscopists ranged from substantial (Cohen's κ=0.71, SE 0.08, 95% CI 0.55-0.86, p<0.005) to borderline almost perfect agreement (Cohen's κ=0.81, SE 0.07, 95% CI 0.68-0.93, p<0.005). Schistocyte quantitation using our new method is simpler than the 2012 ICSH method and had almost perfect agreement. Our finding of moderate inter-observer agreement in quantitating helmet, triangle and crescent schistocytes is applicable to both the ICSH and our newly proposed method. This finding underscores the importance of clinicopathological correlation and repeated examinations in the context of a clinically suspected TMA.
Topics: Cell Count; Erythrocyte Count; Erythrocytes, Abnormal; Humans; Observer Variation; Purpura, Thrombotic Thrombocytopenic; Thrombotic Microangiopathies
PubMed: 33863504
DOI: 10.1016/j.pathol.2021.01.008 -
Health Science Reports Mar 2020Diagnosis of thrombotic microangiopathy (TMA) relies on microscopic schistocyte determination by an experienced microscopist. In addition, schistocytes can be found in...
BACKGROUND AND AIMS
Diagnosis of thrombotic microangiopathy (TMA) relies on microscopic schistocyte determination by an experienced microscopist. In addition, schistocytes can be found in non-TMA-related disorders such as thalassaemia. We aimed to compare the accuracy of the automated haematology analyser Sysmex XN-3000 for schistocyte detection, to that of the microscopy approach, in patients suspected of having schistocytosis.
METHODS
Consecutive blood samples were collected between April 2016 and March 2017 at Siriraj Hospital, Mahidol University, Bangkok, Thailand. Specimens were collected from adults with suspected TMA or with thalassaemia trait and/or disease. All blood samples were examined by both microscopy and the analyser. Samples were considered to be positive for schistocytes (ie, schistocytosis) if they had a schistocyte count ≥1% by microscopy. The analyser's ability to determine schistocytosis was assessed by receiver operating characteristic (ROC) curve. Sensitivity, specificity, positive (PPV), and negative predictive value (NPV) of an appropriate cut-off point were calculated, with manual microscopy as the standard. Quantitative agreement in schistocyte counts between the two approaches was assessed using 95% limits of agreement, Bland-Altman plots, intraclass correlation coefficient, and concordance correlation coefficient.
RESULTS
Ninety-seven blood samples (62 suspected TMA and 35 thalassaemia) were collected. ROC curve analysis of the analyser for determining schistocytosis showed an area under the curve of 0.803 (95% confidence interval, 0.689-0.917, < 0.001). A cut-off point of 0.6% yielded 86.1% sensitivity, 77.8% specificity, 94.4% PPV, and 56.0% NPV. The automated schistocyte count did not quantitatively agree with schistocyte counts by microscopy, neither in all blood specimens (mean of difference: -1.09; 95% limits of agreement, -11.9 to 9.7) nor in the subgroups (TMA, -0.88; 95% limits of agreement, -6.60 to 4.84; thalassaemia, -2.4; 95% limits of agreement, -14.10 to 9.30). The differences in the estimation of fragmented red blood cells between the methods tended to increase at higher schistocyte counts.
CONCLUSION
Sysmex XN-3000 can be used for qualitative measurement of schistocytosis, but should not be used as a quantitative tool for schistocyte counting. Improvements are needed before this analyser's schistocyte detection feature can be recommended for use in clinical practice.
PubMed: 32166186
DOI: 10.1002/hsr2.138 -
Cureus Jul 2022Thrombotic thrombocytopenic purpura (TTP) is a rare and challenging diagnosis that consists of thrombotic microangiopathy due to complete or severe deficiency of...
Thrombotic thrombocytopenic purpura (TTP) is a rare and challenging diagnosis that consists of thrombotic microangiopathy due to complete or severe deficiency of ADAMTS13 protease that can present at any age. It is very important to have a suspicion concerning this disease as mortality can be very high if it goes unnoticed. This case describes a patient that presented with gastrointestinal symptoms and hematuria and was found to have COVID-19 and TTP. We present a case of a 40-year-old female with no past medical history who presented to the Emergency Department with complaints of abdominal pain, nausea, vomiting, and dark urine. The patient workup revealed a platelet count of 4000. The patient was also noted to be COVID-19 positive. Upon further workup, the TTP diagnosis was confirmed. She responded appropriately to plasmapheresis and steroids. COVID-19 seems to be linked to a wide range of hematologic conditions including but not limited to TTP. In view that TTP can have significant mortality if untreated, we must be suspicious about this condition in COVID-19 cases. The aim of this case report is to highlight the importance of having a low threshold for making a diagnosis of TTP if labs are significant for hemolytic anemia. Our aim is also to emphasize that the treatment should be initiated if schistocytes are seen on the peripheral smear without awaiting laboratory results confirming low levels of ADAMTS13, given the fatal nature of the condition if left untreated.
PubMed: 35989804
DOI: 10.7759/cureus.26933